Understanding of mechanisms that control lifespan is among the most challenging biological problems. Although not viewed as a medical condition to be treated, aging is the most prevalent disease-related state. Many complex human diseases are associated with aging, which is both the most significant risk factor and the process that drives the development of these diseases. Clinically, extending lifespan would mean delaying the onset of age-related diseases, such as cancer, neurodegenerative diseases, type II diabetes and sarcopenia. Studies of model organisms and centenarians as well as the use of compounds that extend lifespan in model organisms (e.g., rapamycin) as drugs for multiple human diseases associated with aging suggest that these approaches are feasible. It is also clear that the aging process can be naturally accelerated and delayed (e.g., mammals are characterized by >100-fold difference in lifespan, and it can both increase and decrease during evolution). These differences in lifespan and other traits among mammals are much larger than those among natural isolates of the same species of model organisms, between centenarians and controls, or between wild type and longer-lived mutant organisms identified in various laboratories. Moreover, the observed variation in mammalian lifespan occurs naturally, in contrast to laboratory mutants characterized by extended lifespan but unable to compete in the natural setting. We propose to employ this diversity in lifespan and associated life-history traits to uncover mechanisms that regulate species lifespan in mammals. For this, we will utilize methods of comparative genomics to examine pairs of genomes of closely related short- and long-lived organisms, carry out analysis of lifespan, life-history and other traits across a panel of mammalian tissues and cells using RNA-seq and metabolomics, identify key regulators of lifespan, develop interventions that simultaneously target these regulators, and directly apply these findings to cells and organisms in order to shift short-lived species toward the state of related longer-lived species. We suggest that a better understanding of causal relationships and molecular mechanisms of lifespan control will lead to a better understanding of human diseases of aging and will allow development of treatments that delay the aging process, thereby delaying the onset of human diseases associated with aging.